Morphinoid derivatives as delta-opioid agonists and antagonists

ABSTRACT

Compounds of formula (I) in which R 1  is hydrogen or alkyl; R 2  is hydrogen or one or more alkyl groups; R 3  is R 1  or R 1 X—; wherein R 1  is hydrogen or optionally substituted alkyl, aryl, arylalkyl, cycloalkyl or heterocyclyl and X is a linking group; and R 4  is hydrogen or alkyl; with the proviso that when R 4  is methyl and R 3  is methyl or hydroxyethyl then R 2  is not hydrogen. Are selective delta opioid receptor ligands and therefore of potential therapeutic utility as analgesics and antihyperalgesics for different pain conditions; immunosuppressants to prevent rejection in organ transplant and skin grafts; anti-allergic and anti-inflammatory agents; brain cell protectants; agents for treating drug and alcohol abuse, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy.

[0001] The present invention is concerned with novel morphinoidcompounds, processes for their preparation and their use in medicine.

[0002] The presence of at least three populations of opioid receptors(mu, delta and kappa) is now well established and documented and allthree appear to be present in the central and peripheral nervous systemof many species including man (J. A. H. Lord et al., Nature 1977, 267,495).

[0003] Activation of all three opioid receptor subtypes can lead toantinociception in animal models. In particular, studies with peptidicdelta agonists have indicated that activation of the delta receptorproduces antinociception in rodents, primates and can induce clinicalanalgesia in man (D. E. Moulin et al. Pain, 1985, 23 213). Evidenceexists that suggest a lesser propensity of delta agonists to cause theusual side-effects associated with mu and kappa activation (Galligan etal, J. Pharm. Exp. Ther., 1984, 229, 641).

[0004] WO 96/02545 and WO 97/25331 (SmithKline Beecham SpA) disclosesubstituted monoheterocycle-condensed morphinoid derivatives which arepotent and selective delta opioid agonists and antagonists, including(in WO 97/25331) the compounds:

[0005] We have discovered that certain novel morphinoid compounds aresurprisingly more potent and selective than known delta opioid receptorligands and therefore of potential therapeutic utility as analgesics andantihyperalgesics for different pain condition; immunosuppressants toprevent rejection following organ transplants and skin grafts;anti-allergic and anti-inflammatory agents; brain cell protectants;agents for treating drug and alcohol abuse, cardiovascular andrespiratory diseases, cough, mental illness and epilepsy; agents fortreating gastrointestinal disorders such as gastritis, diarrhoea andirritable bowel syndrome; and, in general, for the treatment of thosepathological conditions which customarily can be treated with agonistsand antagonists of the delta opioid receptor.

[0006] According to the present invention, there is provided a compound,or a solvate or salt thereof, of formula (I):

[0007] in which:

[0008] R₁ is hydrogen or alkyl;

[0009] R₂ is hydrogen or one or more alkyl groups;

[0010] R₃ is R_(t) or R_(t)X—; wherein R_(t) is hydrogen or optionallysubstituted alkyl, aryl, aryl-alkyl, cycloalkyl or heterocyclyl, and Xis a linking group; and

[0011] R₄ is hydrogen or alkyl;

[0012] with the proviso that when R₄ is methyl and R₃ is methyl orhydroxyethyl then R₂ is not hydrogen.

[0013] Alkyl groups, including alkyl groups that are part of, forexample, alkoxy or acyl groups, typically contain 1 to 6 carbon atoms,and may be linear or branched, such as methyl, ethyl, i-propyl, t-butyl,or i-pentyl. Aryl groups are typically phenyl, but may include bicyclicgroups such as naphthyl. Aryl-alkyl groups include benzyl andphenylethyl. Cycloalkyl groups typically contain from 3 to 7 carbonatoms and include cyclobutyl and cyclohexyl. Heterocyclic groups may bemonocyclic 5 to 7 membered rings containing up to three hetero atoms,such as pyridyl, pyrazinyl, pyrimidinyl, furyl, or imidazolyl,especially pyridyl, pyrimidyl; or bicyclic, especially heterocyclicrings fused to benzene rings, such as benzoxazolyl or benzimidazolyl.Aryl, cycloalkyl and heterocyclic groups may be optionally substitutedby up to three substituents, which may suitably be selected from aryl,alkyl, alkoxy, halogen, hydroxy, oxo and cyano, or by linkedsubstituents such as dioxymethylene.

[0014] R₁ and R₄ are typically hydrogen or alkyl, especially methyl.

[0015] Typical R₂ groups include hydrogen and alkyl, especially methyl,which may be present as dimethyl.

[0016] A particular group of compounds are those wherein when R₃ ismethyl or hydroxyethyl then R₂ is not hydrogen.

[0017] R₃ groups are preferably R_(t), R_(t)CO—, R_(t)NHCO—, orR_(t)SO₂—.

[0018] When R_(t) is an alkyl group suitable alkyl groups includemethyl, ethyl, i-propyl, i-butyl, t-butyl, n-butyl, and i-pentyl,especially i-propyl. Alkyl groups may be substituted, for example byhydroxy, suitably as hydroxyethyl.

[0019] When R_(t) is an aryl or aryl-alkyl group, suitable aryl andaryl-alkyl groups include in particular phenyl, benzyl and phenylethyl.

[0020] When R_(t) is a cycloalkyl group, suitable cycloalkyl groupsinclude cyclobutyl and cyclohexyl, especially cyclohexyl, and suitableheterocyclyl groups include furyl, pyridyl, pyrimidyl, benzoxazolyl,benzimidazolyl, and imidazolyl, especially pyridyl, pyrimidyl,benzoxazolyl, benzimidazolyl, and imidazolyl, more especially pyridyland pyrimidyl.

[0021] Suitable values for X include —CO—, —OCO—, —NHCO—, —SO₂—, —CONH—,and —OCONH—, particularly —CO—, —NHCO—, and —SO₂—.

[0022] When R₃ is a group R_(t)X— suitable groups include ethyl-OOC—,t-butyl-O—CO—, i-butyl-CO—, n-butyl-CO—, i-pentyl-CO—, phenyl-CO—,benzyl-CO—, phenylethyl-CO—, cyclohexyl-CO—, methyl-NH—CO—,ethyl-NH—CO—, methyl-SO₂— and formyl. Especially suitable arephenyl-CO—, i-butyl-CO—, i-pentyl-CO—, benzyl-CO—, cyclohexyl-CO—,ethyl-NH—CO—, methanesulphonyl and formyl. Other suitable groups areethyl-CO—, furyl-CO— and cyclobutyl-CO—.

[0023] Suitable optional substituents for cyclic R₃ groups include oxo,dioxymethylene, bromo, chloro, fluoro, hydroxy, cyano, methyl, methoxy,t-butyl and phenyl, especially dioxymethylene, chloro, fluoro, hydroxy,cyano, methyl, methoxy and t-butyl. A further suitable optionalsubstituent is trifluoromethyl.

[0024] In a particular aspect R₃ is selected from hydrogen, methyl,ethyl, i-propyl, i-butyl, t-butyl, n-butyl, i-pentyl, hydroxyethyl,phenyl, benzyl, phenylethyl, cyclohexyl, cyclobutyl, pyridyl, pyrimidyl,benzoxazolyl, benzimidazolyl, imidazolyl, ethyl-CO—, ethyl-OOC—,t-butyl-O—CO—, i-butyl-CO—, n-butyl-CO—, i-pentyl-CO—, phenyl-CO—,furyl-CO—, benzyl-CO—, phenylethyl-CO—, cyclohexyl-CO—, cyclobutyl-CO—,methyl-NH—CO, ethyl-NH—CO—, methyl-SO₂— and formyl, where the cyclic R₃groups are optionally substituted by one or more of oxo, dioxymethylene,bromo, chloro, fluoro, hydroxy, cyano, methyl, methoxy, t-butyl,trifluoromethyl and phenyl.

[0025] In another aspect R₃ is selected from hydrogen, methyl, ethyl,i-propyl, i-butyl, t-butyl, n-butyl, i-pentyl, hydroxyethyl, phenyl,benzyl, phenylethyl, cyclohexyl, pyridyl, pyrimidyl, benzoxazolyl,benzimidazolyl, imidazolyl, ethyl-OOC—, t-butyl-O—CO—, i-butyl-CO—,n-butyl-CO—, i-pentyl-CO—, phenyl-CO—, benzyl-CO—, phenylethyl-CO—,cyclohexyl-CO—, methyl-NH—CO, ethyl-NH—CO—, methyl-SO₂— and formyl,where the cyclic R₃ groups are optionally substituted by one or more ofoxo, dioxymethylene, bromo, chloro, fluoro, hydroxy, cyano, methyl,methoxy, t-butyl, and phenyl.

[0026] In a further aspect R₃ is selected from hydrogen or optionallysubstituted alkyl, aryl, aryl-alkyl, cycloalkyl or heterocyclyl; orhydrogen or an optionally substituted alkyl, aryl, aryl-alkyl,cycloalkyl or heterocyclic group linked to N via a >C═O, —N—CO— or >SO₂group.

[0027] The compounds of formula (I), or their salts or solvates, arepreferably in pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, of apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels.

[0028] A substantially pure form will generally contain at least 50%(excluding normal pharmaceutical additives), preferably 75%, morepreferably 90% and still more preferably 95% of the compound of formula(I) or its salt or solvate.

[0029] One preferred pharmaceutically acceptable form is the crystallineform, including such form in a pharmaceutical composition. In the caseof salts and solvates the additional ionic and solvent moieties mustalso be non-toxic.

[0030] Examples of pharmaceutically acceptable salts of a compound offormula (I) include the acid addition salts with the conventionalpharmaceutical acids, for example, maleic, hydrochloric, hydrobromic,phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic,tartaric, succinic, benzoic, ascorbic and methanesulphonic.

[0031] Salts or solvates of the compounds of formula (I) which are notpharmaceutically acceptable may be useful as intermediates in theproduction of pharmaceutically acceptable salts or solvates. Accordinglysuch salts or solvates also form part of this invention.

[0032] The compounds of formula (I) may exists in more than onestereoisomeric form, and the invention extends to all such forms as wellas to their mixtures thereof, including racemates.

[0033] The compounds of formula (I), or salts or solvates thereof, maybe prepared by the methods illustrated in the following general reactionschemes, or by modification thereof, using readily available startingmaterials, reagents and conventional synthetic procedures. These methodsconstitute a further aspect of the invention. If a particular enantiomerof a compound of the present invention is desired, it may be synthesisedstarting from the desired enantiomer of the starting material andperforming reactions not involving racemization processes or it may beprepared by chiral synthesis, or by derivation with a chiral auxiliary,where the resulting diastereomeric mixture is separated and theauxiliary group cleaved to provide the pure desired enantiomers.Alternatively, where the molecule contains a basic functional group,such as amino, or an acidic functional group, such as carboxy,diastereomeric salts are formed with an appropriate optically activeacid or base, followed by resolution of diastereomeric salts byfractional crystallization and subsequent recovery of the pureenantiomers.

[0034] The compounds of formula (I) and pharmaceutically acceptablederivatives thereof may be prepared by the processes describedhereinafter, said processes constituting a further aspect of theinvention. In the following description, the groups R₁, R₂, R₃ and R₄are as defined for compounds of formula (I) unless otherwise stated.

[0035] Compounds of formula (I) may be prepared by reaction of acylcompounds of formula (II) with piperazines of formula (III) using thefollowing reaction Scheme 1:

[0036] wherein R₁, R₂, R₃ and R₄ are as hereinbefore defined forcompounds of formula (I) and L is a leaving group, for example halo,especially chloro; followed, if so desired, by conversion to a saltand/or solvate thereof.

[0037] The reaction of a compound of formula (II) with a compound offormula (III) is suitably carried out in the presence of a base, forexample an organic base, such as an amine, for example triethylamine,diisopropylethylamine, pyridine or dicyclohexylamine. A particular aminethat may be mentioned is triethylamine. The reaction is suitably carriedout in the presence of a solvent, for example an aprotic solvent such asN,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidinone, ordimethoxyethane; or a chlorinated solvent such as dichloroethane ordichloromethane. A particular solvent that may be mentioned istetrahydrofuran. Suitable reaction temperatures include 10-40° C., moreparticularly 15-25° C.

[0038] Compounds of formula (II) may be prepared according to processesknown in the art for the preparation of acyl groups, for example S.Patai, The Chemistry of Acyl Halides, pp 35-78, Interscience, New York,1972. The compounds of formula (II) when L is chloro may be obtained forexample by reacting a ketone of formula (IV) with a hydrazone of formula(V), in the presence of Zn and CH₃COONa in CH₃COOH as solvent (KhimiyaGeterot. Soed., 1972, 342), followed by treatment with sodium hydroxideto give the sodium carboxylate. Conversion to the corresponding acylchloride is achieved by treatment with oxalyl chloride, as shown inscheme 2:

[0039] Suitable starting materials of formula (IV) include the morphinanhydrocodone (R₁ and R₄ are methyl), which is commercially available, andother compounds which are known in the literature. The othersubstituents specified for R₁ and R₄ in formula (I) may incorporatedand/or converted by conventional substitution reactions before or afterthe coupling of compounds (II) and (III). For example, a compound offormula (I) or formula (II) in which R₁ is alkyl may be converted intoanother compound of formula (I) or formula (II) respectively in which R₁is hydrogen by conventional methods. Similarly a compound of formula (I)or formula (II) in which R₁ is hydrogen may be converted into a compoundof formula (I) or formula (II) in which R₁ is alkyl by conventionalsubstitution reactions. Similarly compounds of formula (I) or formula(II) in which R₄ is alkyl may be converted to the correspondingcompounds in which R₄ is hydrogen, and compounds in which R₄ is hydrogenmay be converted to corresponding compounds in which R₄ is alkyl.

[0040] The compounds of formula (I) may be alternatively obtainedstarting from ketones of formula (IV) and hydrazones of formula (VI)prepared using as starting materialcompounds prepared by reactingethylacetoacetate with the appropriate substituted piperazines ofgeneral formula (III). The resulting acetoacetamides of general formula(VII) are in turn reacted with phenyldiazonium salt to obtain thecorresponding hydrazones of general formula (VI) as shown in Scheme 3:

[0041] The substituted piperazines of formula (V) are eithercommercially available or readily synthesised by conventional methodsfrom commercially available materials.

[0042] Alternatively, compounds of general formula (I) can be alsoobtained from compounds of general formula (I′), in which R₁ is alkyland R₃ is hydrogen, by alkylation or acylation of the piperazine basicnitrogen using conventional methods. Compounds of general formula (I′)can be in turn obtained from compounds of general formula (I″),synthesised as described above for compounds of general formula (I),where R₃″ is a suitable protecting group, for example,9-fluorenylmethoxycarbonyl (FMOC) or N-t-butoxycarbonyl (BOC), that canbe easily removed by conventional methods to give the desired compoundsof general formula (I′) as shown in Scheme 4.

[0043] In a further aspect the present invention provides for novelintermediates of formulae (II), (II′), (III), (V), (VI), (VII), (I′) and(I″).

[0044] The compounds of formula (I) may be converted into theirpharmaceutically acceptable salts by reaction with the appropriateorganic or mineral acids.

[0045] Solvates, including hydrates, of the compounds of formula (I) maybe formed by crystallization or recrystallization from the appropriatesolvent. For example, hydrates may be formed by crystallization orrecrystallization from aqueous solutions, or solutions in organicsolvents containing water.

[0046] In general compounds of formula (I) acting as selective deltareceptor ligands may be useful as analgesics and antihyperalgesics fordifferent pain conditions, immunosuppressants to prevent rejection inorgan transplant and skin graft, anti-allergic and anti-inflammatoryagents, brain cell protectant, for the treatment of drug and alcoholabuse, to decrease gastric secretion, for the treatment of diarrhoea,cardiovascular and respiratory diseases, cough and respiratorydepression, mental illness, epileptic seizures and other neurologicdisorders (herein after referred to as ‘Conditions’). In particular, theactivity of the compounds of formula (I) as delta agonists in standardtests indicates that they are of potential therapeutic utility asanalgesic agents for the amelioration or elimination of pain.

[0047] Accordingly the present invention provides a method for thetreatment and/or prophylaxis of one or more of the Conditions inmammals, particularly humans, which comprises administering to themammal in need of such treatment and/or prophylaxis an effective amountof a compound of formula (I) or a pharmaceutically acceptable salt orsolvate thereof.

[0048] The present invention also provides a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, for use as anactive therapeutic substance. In particular the present invention alsoprovides a compound of formula (I) or a pharmaceutically acceptable saltthereof for use in the treatment and/or propylaxis of one or more of theConditions.

[0049] The present invention further provides a pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.

[0050] The present invention also provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,in the manufacture of a medicament for the treatment and/or prophylaxisof one or more of the Conditions.

[0051] Such a medicament, and a composition of this invention, may beprepared by admixture of a compound of the invention with an appropriatecarrier. It may contain a diluent, binder, filler, disintegrant,flavouring agent, colouring agent, lubricant or preservative inconventional manner.

[0052] These conventional excipients may be employed for example as inthe preparation of compositions of known agents for treating theConditions.

[0053] Preferably, a pharmaceutical composition of the invention is inunit dosage form and in a form adapted for use in the medical orveterinarial fields. For example, such preparations may be in a packform accompanied by written or printed instructions for use as an agentin the treatment of the Conditions.

[0054] The suitable dosage range for the compounds of the inventiondepends on the compound to be employed and on the condition of thepatient. It will also depend, inter alia, upon the relation of potencyto absorbability and the frequency and route of administration.

[0055] The compound or composition of the invention may be formulatedfor administration by any route, and is preferably in unit dosage formor in a form that a human patient may administer to himself in a singledosage. Advantageously, the composition is suitable for oral, rectal,topical, parenteral, intravenous or intramuscular administration.Preparations may be designed to give slow release of the activeingredient.

[0056] Compositions may, for example, be in the form of tablets,capsules, sachets, vials, powders, granules, lozenges, reconstitutablepowders, or liquid preparations, for example solutions or suspensions,or suppositories.

[0057] The compositions, for example those suitable for oraladministration, may contain conventional excipients such as bindingagents, for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable setting agents such as sodiumlauryl sulphate.

[0058] Solid compositions may be obtained by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. When the composition is in theform of a tablet, powder, or lozenge, any carrier suitable forformulating solid pharmaceutical compositions may be used, examplesbeing magnesium stearate, starch, glucose, lactose, sucrose, rice flourand chalk. Tablets may be coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.The composition may also be in the form of an ingestible capsule, forexample of gelatin containing the compound, if desired with a carrier orother excipients.

[0059] Compositions for oral administration as liquids may be in theform of, for example, emulsions, syrups, or elixirs, or may be presentedas a dry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may contain conventional additivessuch as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose,aluminium stearate gel, hydrogenated edible fats; emulsifying agents,for example lecithin, sorbitan monooleate, or acacia; aqueous ornon-aqueous vehicles, which include edible oils, for example almond oil,fractionated coconut oil, oily esters, for example esters of glycerine,or propylene glycol, or ethyl alcohol, glycerine, water or normalsaline; preservatives, for example methyl or propyl p-hydroxybenzoate orsorbic acid; and if desired conventional flavouring or colouring agents.

[0060] The compounds of this invention may also be administered by anon-oral route. In accordance with routine pharmaceutical procedure, thecompositions may be formulated, for example for rectal administration asa suppository. They may also be formulated for presentation in aninjectable form in an aqueous or non-aqueous solution, suspension oremulsion in a pharmaceutically acceptable liquid, e.g. sterilepyrogen-free water or a parenterally acceptable oil or a mixture ofliquids. The liquid may contain bacteriostatic agents, anti-oxidants orother preservatives, buffers or solutes to render the solution isotonicwith the blood, thickening agents, suspending agents or otherpharmaceutically acceptable additives. Such forms will be presented inunit dose form such as ampoules or disposable injection devices or inmulti-dose forms such as a bottle from which the appropriate dose may bewithdrawn or a solid form or concentrate which can be used to prepare aninjectable formulation.

[0061] The compounds of this invention may also be administered byinhalation, via the nasal or oral routes. Such administration can becarried out with a spray formulation comprising a compound of theinvention and a suitable carrier, optionally suspended in, for example,a hydrocarbon propellant.

[0062] Preferred spray formulations comprise micronised compoundparticles in combination with a surfactant, solvent or a dispersingagent to prevent the sedimentation of suspended particles. Preferably,the compound particle size is from about 2 to 10 microns.

[0063] A further mode of administration of the compounds of theinvention comprises. transdermal delivery utilising a skin-patchformulation. A preferred formulation comprises a compound of theinvention dispersed in a pressure sensitive adhesive which adheres tothe skin, thereby permitting the compound to diffuse from the adhesivethrough the skin for delivery to the patient. For a constant rate ofpercutaneous absorption, pressure sensitive adhesives known in the artsuch as natural rubber or silicone can be used.

[0064] As mentioned above, the effective dose of compound depends on theparticular compound employed, the condition of the patient and on thefrequency and route of administration. A unit dose will generallycontain from 20 to 1000 mg and preferably will contain from 30 to 500mg, in particular 50, 100, 150, 200, 250,300, 350, 400, 450, or 500 mg.The composition may be administered once or more times a day for example2, 3 or 4 times daily, and the total daily dose for a 70 kg adult willnormally be in the range 100 to 3000 mg. Alternatively the unit dosewill contain from 2 to 20 mg of active ingredient and be administered inmultiples, if desired, to give the preceding daily dose.

[0065] No unacceptable toxicological effects are expected with compoundsof the invention when administered in accordance with the invention.

[0066] The activity of the compounds of the present invention asselective delta ligands is determined in radioligand binding assays asdescribed below.

Pharmacological Data

[0067] The activity of the compounds of the present invention asselective delta ligands is determined in radioligand binding assaysusing cloned human delta, mu and kappa opioid receptors stably expressedin cell lines as described below.

[0068] CHO cells were subjected to stable transfection with cDNAencoding the human delta and mu opioid receptors. Clones were grown insuspension culture in serum free media. Selection was performed bygrowth in the absence of nucleotides.

[0069] Human kappa opioid receptors were stably expressed in HEK cells.Cells were grown in adhesion in E-MEM supplemented with 10% FBS and 2 mML-glutamine, G418 was included for selection.

[0070] Membranes were prepared as previously described (J. Med. Chem.1997, 40 3192). The binding of the preferential delta ligand[³H]-[D-Ala²,D-Leu⁵]-enkephalin (DADLE) was evaluated at its K_(D)concentration (0.7 nM). The binding of the mu ligand [³H]-DAMGO (Eur. J.Pharmacol., 1989, 166, 213) and of the kappa ligand [³H]-U69593(Excerpta Medica, 1990, 211) were carried out at 0.5 nM. Non specificbinding was determined in the presence of 10 uM of naloxone. Bindingdata were expressed as percentage of inhibition and fitted the followingequation: f(x)=100·X/(IC₅₀+X) where X is the cold drug concentrationvalue. The IC₅₀ values obtained were used to calculate the inhibitoryconstants (K_(i)) according to the Cheng and Prusoff relation (Biochem.Pharmacol., 1973, 22, 3099).

[0071] The most potent compounds described in the present inventionshowed affinities for the delta receptor ranging from 0.3 to 10 nM withdelta selectivity ranging from 15 to 400 times in respect to the otheropioid receptor types.

[0072] For example, the compounds of Examples 6 and 23 show a Kidelta=1.0 nM (Ki mu/Ki delta=437) and Ki delta=0.6 (Ki mu/Kidelta=1010), respectively.

[0073] The following Procedures X and Y and Example 15 illustrate thepreparation of compounds of general formula (I) of the presentinvention. The compounds of the Examples 1 to 14 and 16 to 39 and 48 to52 are obtained using the general procedure as described in Example 15(Method A), starting from the corresponding acyl chloride of generalformula (II) and the corresponding known substituted piperazines ofgeneral formula (III). Procedures X and Y illustrate the preparation ofintermediates of formulae (II) and (V).

[0074] The compounds of the remaining Examples 41 to 47 are obtainedusing the same procedure as described in Procedures P and Q and Example40 (Method B), starting from the corresponding acyl chloride and thepiperazines of general formula (I′) by removal of a protecting groupfrom compounds of general formula (I″,) synthesised as described aboveusing Method A.

[0075] The compounds obtained in the Examples 1 to 52 are summarised inTable 1.

Procedure X Preparation of sodium salt of [8R-(4bS*,8α,8a β,12bβ)]-7,10-dimethyl-1-methoxy-1-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]-pyrrolo[2,3-g]isoquinoline-11-carboxylicacid (compound of Formula II′ wherein R₁=Me, and R₄=Me).

[0076] To a solution of hydrocodeinone (25 g, MW 335.8, 74 mmol) in 400ml of AcOH, AcONa (20 g, MW 82, 224 mmol) and3-oxo-2-(phenyl-hydrazono)-butyric acid ethyl ester (V, see below) (34.6g, MW 234.25, 147 mmol) were added. The mixture was heated to 50-60° C.and then Zn (16 g, MW 65.4, 244 mmol) was added portionwise, maintainingthe temperature below 90° C. The mixture was then heated to 100° C. for8 hours. The slurry was poured in a mixture containing 30% NH₄OH (200ml) and 400 g of brine and then extracted with AcOEt (3×200 ml). Theorganic layer was dried over Na₂SO₄ and the solvent was removed undervacuum. The residue was purified by chromatography on silica gel elutingwith AcOEt/MeOH/NH₄OH 90/10/1 to afford the [8R-(4bS*,8 α,8a β,12bβ]-7,10-dimethyl-1-methoxy-11-ethyloxycarbonyl-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]-pyrrolo[2,3-g]isoquinoline(12 g, PM 408.5, 30 mmol).

[0077] A mixture of this compound (5 g, 12 mmol) and 1M NaOH (30 ml) in60 ml of EtOH 96% was stirred at 80° C. for 5 hours. The solvent wasevaporated under vacuum and the residue was triturated in water (30 ml).After filtration, the solid was dried under vacuum at 50° C. for onenight affording the title compound (4 g, MW 402.4, 10 mmol).

[0078] Treatment with oxalyl chloride (see Method A, below) provides thecompound of Formula II wherein R₁=Me, R₄=Me, and L=Cl.

[0079] Procedure Y

[0080] 3-Oxo-2-(phenyl-hydrazono)-butyric acid ethyl ester (Compound V)

[0081] In a flask containing 250 ml of 5 N HCl at the temperature of0-5° C., 46.5 g of aniline (0.5 moles) were added under nitrogen flow.Then a solution of 36.5 g of NaNO₂ (0.53 moles) in 125 ml of water wasadded dropwise maintaining the temperature at 5-10° C. At the end of theaddition the solution was adjusted to pH 4-5 with solid sodium acetate.The obtained solution was then transferred in a dropping funnel andadded dropwise to a solution of ethylacetoacetate (65 g, 0.5 moles) in375 ml of EtOH (95°), 100 ml of water and sodium acetate (0.73 moles)maintaining the temperature below 5-10° C. Then the reaction was warmedup to room temperature, and it was further stirred for two hours. 500 mlof water were added and after 30 minutes stirring, the suspension wasfiltered under vacuum. The orange-yellow solid was dried under vacuum atroom temperature overnight to obtain 68 g of the title compound.

Example 15 (Method A) [8R-(4bS*,8 α,8a β,12bβ)]-11-(4-(4-Chlorophenyl)piperazin-1-yl)carbonyl-1-methoxy-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]-pyrrolo[2,3-g]isoquinoline

[0082] Oxalyl chloride (4.0 g, 31 mmol) was added dropwise at 0° C. to asuspension of sodium salt prepared as described above in Procedure X(1.7 g, MW 402, 4.23 mmol) in THF (300 ml). The mixture was stirred 4hours at room temperature (or to complete solution) and then wasconcentrated under vacuum. The residue was dissolved in THF (100 ml) andthe solution of 4-chlorophenylpiperazine hydrochloride (1.25 g, MW269.6, 4.65 mmol) in THF (5 ml) and TEA (2.6 ml) were added dropwise.The mixture was stirred at room temperature for 4 hours, then thesolvent was removed in vacuo. The residue was dissolved in AcOEt (50ml×2) and washed with 1N NaOH (50 ml). The organic layer was dried overNa₂SO₄ and evaporated under vacuum. The product was purified bychromatography on silica gel eluting with AcOEt/MeOH/NH₄OH 90/10/1 toafford mg 0.8 g of the title compound.

Procedure P [8R-(4b S, 8 α, 8a β 12bβ)]-11-(4-Tertbutoxycarbonylpiperazin-1-yl)carbonyl-1-methoxy-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-(9H)4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline(Compound of Formula I″, R₁=Me, R₄=Me, R₂=H, R₃=tert-butoxycarbonyl)

[0083] Oxalyl chloride (1.1 ml, 12 mmol) was added dropwise at 0° C. toa suspension of sodium salt prepared as described above in Procedure X(0.5 g, MW 402, 1.2 mmol) in THF (30 ml). The mixture was stirred 4hours at room temperature and then was concentrated under vacuum.

[0084] The residue was dissolved in THF (10 ml) then N-BOC-piperazine(II) (mg 250, MW 185, 1.3 mmol) in THF (2 ml) and TEA (500 μl, 3.6 mmol)were added. The mixture was stirred at room temperature for 4 hours,then the solvent was removed in vacuo. The residue was dissolved inAcOEt (20 ml×2) and washed with 1N NaOH (5 ml). The organic layer wasdried over Na₂SO₄ and evaporated under vacuum. The product was purifiedby chromatography on silica gel eluting with AcOEt/MeOH/NH₄OH 90/10/1 toafford mg 500 of the title compound.

Procedure Q [8R-(4b S, 8 α, 8a β, 12bβ)]-11-(piperazin-1-yl)carbonyl-1-methoxy-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-(9H)4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline(Compound of Formula I′, R₁=Me, R₄=Me, R₂=H)

[0085] N-BOC derivative of Procedure P (500 mg, MW 520.63, 1 mmol) wasdissolved in CH₂Cl₂ (8 ml) and then TFA (0.5 ml) was added slowly. Thereaction was stirred overnight at room temperature, and then the solventand the excess of TFA were evaporated under vacuo. The residue wasdissolved in CH₂Cl₂ (10 ml×2) and washed with a saturated solution ofNa₂CO₃ (10 ml). The organic layer was dried over Na₂SO₄ and evaporatedunder vacuum. The product was triturated with Et₂O to give the titlecompound (300 mg, MW 420, 0.71 mmol).

Example 40 (Method B) [8R-(4b S, 8 α, 8a β, 12bβ)]-11-[4-(2,4-Dimethoxybenzoyl)piperazin-1-yl]carbonyl-1-methoxy-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-(9H)4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline

[0086] To a solution of the piperazino derivative prepared in ProcedureQ (100 mg, MW 420, 0.26 mmol) in THF (3 ml), TEA (37 μl, MW 101, 0.26mmol) and 2,4-dimethoxybenzoyl chloride (52 mg, MW 200.62, 0.26 mmol)were added. The mixture was stirred at room temperature for 15 hours. 1NNaOH (2 ml ) was added and the mixture was extracted with AcOEt (6ml×2). The organic layer was dried over Na₂SO₄ and evaporated undervacuum. The product was purified by chromatography on silica gel elutingwith AcOEt/MeOH/NH₄OH 80/20/1 to afford the title compound (68 mg, MW612, 0.11 mmol). TABLE 1

mass ESI POS; AQA; solvent: [a]_(D) ^(20§)/ methanol/spray 3 kV/ Ex. R₁R₂ R₃ R₄ (MP ° C.) skimmer: 20 V/probe 135 C. 1 Me H CH₂Ph Me −384.72 *538 (M+.); 447; (172.5-177.4) 405; 379; 363; 175; 146; 91 2 Me H Ph Me *524 (M+.); 405; 390; 379; 362; 161; 145; 132 3 Me H i-Pr Me −431.9 * 490(M+.); 405; (166.3-167.7) 363; 98 5 Me H 2-Py Me −461.4 526 (MH+.)(253-255) 5 Me H 2,6-Me—Ph Me (165-168) * 552 (M+.); 405; 379; 362; 189;173; 160 6 Me H 2,4-Me—Ph Me (173-175) * 552 (M+.); 379; 363; 190; 173;160 7 Me H 2-Me—Ph Me — 539 (MH+) 8 Me H Cy Me (130-132) 531 (MH+) 9 MeH 4-MeO—Ph Me −486.2 * 554 (M+.); 363; 192; 175; 162; 150 10 Me H3,4-(OCH₂O)— Me * 582 (M+.), 447, PhCH₂ 379; 363; 219; 190; 176; 135 11Me H COPh Me −263.0 553 (MH+) 12 Me H 4-F—Ph Me 543 (MH+) 13 Me H2-MeO—Ph Me 555 (MH+) 14 Me H 2-Cl—Ph Me — 559 (MH+) 15 Me H 4-Cl—Ph Me−435.8 559 (MH+) (189-192) 16 Me H 4-t-Bu—Ph Me — 581 (MH+) 17 Me H4-Cl-PhCH₂ Me — 574 (MH+) 18 Me H PhCH₂CH₂ Me −421.7 553 (MH+) (259-260)19 Me H 4-F—PhCH₂ Me 557 (MH+) 20 Me H 4-MeO-PhCH₂ Me −359.6 569 (MH+)(150-152) 21 Me H 3-Me—PhCH₂ Me — 553 (MH+) 22 Me H 4-Me—PhCH₂ Me — 553(MH+) 23 Me H 2,4-MeO—Ph Me −388.5 585 (MH+) (155-160) 24 Me 3-Me Ph Me— 539 (MH+) 25 Me H CHO Me −473.5 477 (MH+) (205-210) 26 Me H 3-Cl—Ph Me— 559 (MH+) 27 Me H 2-MeO-5-Cl—Ph Me — 589 (MH+) 28 Me 3,5- H Me — 477(MH+) Me (cis) 29 Me H 3-Cl—Ph Me (165-167) 559 (MH+) 30 Me H 4-OH—Ph Me— 541 (MH+) 31 Me H 4-Cl—PhCO Me — 588 (MH+) 32 Me H 4-MeO—PhCO Me — 583(MH+) 33 Me H MeSO₂ Me — 527 (MH+) 34 Me H 4-CN—Ph Me — 550 (MH+) 35 MeH MeCH₂NHCO Me — 582 (MH+) 36 Me H

Me — 527 (MH+) 37 Me H PhCH₂CO Me — 567 (MH+) 38 Me H

Me — 547 (MH+) 39 Me H CH₃(CH₂)₃CO Me — 533 (MH+) 40 Me H 2,4-MeO—PhCOMe −421.5 613 (MH+) (190-193) 41 Me H i-BuCO Me — 533 (MH+) 42 Me HPhCH₂CH₂CO Me — 581 (MH+) 43 Me H CyCO Me — 559 (MH+) 44 Me H CH₃CH₂COMe 505 (MH+) 45 Me H

Me 531 (MH+) 46 Me H

Me 543 (MH+) 47 Me H

Me 583 (MH+) 48 Me H

Me 551 (MH+) 49 Me H

Me 594 (MH+) 50 Me H

Me 628 (MH+) 51 Me H

Me 527 (MH+) 52 Me H

Me 594 (MH+)

[0087] TABLE 3 (II)

(III)

Compound (III) Ex R₂ R₃ 1 H CH₂Ph 2 H Ph 3 H i-Pr 4 H 2-Py 5 H 2,6-Me—Ph6 H 2,4-Me—Ph 7 H 2-Me—Ph 8 H Cy 9 H 4-MeO—Ph 10 H 3,4-(OCH₂O)—PhCH₂ 11H COPh 12 H 4-F—Ph 13 H 2-MeO—Ph 14 H 2-Cl—Ph 15 H 4-Cl—Ph 16 H4-t-Bu—Ph 17 H 4-Cl—PhCH₂ 18 H PhCH₂CH₂ 19 H 4-F—PhCH₂ 20 H 4-MeO—PhCH₂21 H 3-Me—PhCH₂ 22 H 4-Me—PhCH₂ 23 H 2,4-MeO—Ph 24 3-Me Ph 25 H CHO 26 H3-Cl—Ph 27 H 2-MeO-5-Cl—Ph 28 3,5-Me (cis) H 29 H 3-Cl—Ph 30 H 4-OH—Ph31 H 4-Cl—PhCO 32 H 4-MeO—PhCO 33 H MeSO₂ 34 H 4-CN—Ph 35 H MeCH₂NHCO 36H

37 H PhCH₂CO 38 H

39 H CH₃(CH₂)₃CO 48 H

49 H

50 H

51 H

52 H

[0088] Examples 40-47 are prepared according to Method B by reacting thecompound of formula (I′) wherein R₁=Me, R₄=Me and R₂=H (preparedaccording to Procedure Q):

[0089] with the appropriate acylating reagent as indicated in Table 4.TABLE 4 Ex Acylating reagent 40 2,4-MeO—PhCOCl 41 i-BuCO 42 PhCH₂CH₂COCl43 CyCOCl 44 CH₃CH₂COCl 45

46

47

1. A compound, or a solvate or salt thereof, of formula (I):

in which: R₁ is hydrogen or alkyl; R₂ is hydrogen or one or more alkylgroups; R₃ is R_(t) or R_(t)X—; wherein R_(t) is hydrogen or optionallysubstituted alkyl, aryl, aryl-alkyl, cycloalkyl or heterocyclyl and X isa linking group; and R₄ is hydrogen or alkyl; with the proviso that whenR₄ is methyl and R₃ is methyl or hydroxyethyl, then R₂ is not hydrogen.2. A compound according to claim 1 in which R_(t) is hydrogen;optionally substituted methyl, ethyl, i-propyl, i-butyl, t-butyl,n-butyl, or i-pentyl; optionally substituted phenyl, benzyl orphenylethyl; optionally substituted cyclobutyl or cyclohexyl; oroptionally substituted furyl, pyridyl, pyrimidyl, benzoxazolyl,benzimidazolyl or imidazolyl.
 3. A compound according to claim 1 inwhich R₃ is selected from hydrogen, methyl, ethyl, i-propyl, i-butyl,t-butyl, n-butyl, i-pentyl, hydroxyethyl, phenyl, benzyl, phenylethyl,cyclohexyl, cyclobutyl, pyridyl, pyrimidyl, benzoxazolyl,benzimidazolyl, imidazolyl, ethyl-CO—, ethyl-OOC—, t-butyl-O—CO—,i-butyl-CO—, n-butyl-CO—, i-pentyl-CO—, phenyl-CO—, furyl-CO—,benzyl-CO—, phenylethyl-CO—, cyclohexyl-CO—, cyclobutyl-CO—,methyl-NH—CO, ethyl-NH—CO—, methyl-SO₂— and formyl, where the cyclic R₃groups are optionally substituted by one or more of oxo, dioxymethylene,bromo, chloro, fluoro, hydroxy, cyano, methyl, methoxy, t-butyl,trifluoromethyl and phenyl.
 4. A compound according to any one of claimsclaim 1 to 3 in which R₂ is selected from hydrogen, methyl and dimethyl.5. A compound according to any one of claims 1 to 4 in which R₁ and R₄are independently selected from hydrogen and methyl.
 6. A compoundaccording to claim 1 which is any one of compounds 1 to 52 in theChemical Table herein.
 7. A method for the treatment and/or prophylaxisof one or more of the Conditions in mammals, particularly humans, whichcomprises administering to the mammal in need of such treatment and/orprophylaxis an effective amount of a compound according to any one ofclaims 1 to 5 or a pharmaceutically acceptable salt or solvate thereof.8. A compound according to any one of claims 1 to 5, or apharmaceutically acceptable salt or solvate thereof, as an activetherapeutic substance.
 9. Use of a compound according to any one ofclaims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof,in the manufacture of a medicament for the treatment and/or prophylaxisof one or more of the Conditions.
 10. A process for the preparation of acompound of formula (I) according to claim 1 which process comprises:reacting a compound of formula (II):

 with a compound of formula (III):

 and, if desired, converting to a salt and/or solvate thereof; wherein Lis a leaving group and R₁, R₂, R₃ and R₄, are as defined in claim 1.